Abstract
The protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that are uniquely activated by proteolysis. PARs mediate hemostasis, thrombosis, inflammation, embryonic development and progression of certain malignant cancers. The family of PARs include four members: PAR1, PAR2, PAR3 and PAR4. PARs harbor a cryptic ligand sequence within their N-terminus that is exposed following proteolytic cleavage. The newly formed PAR Nterminus functions as a tethered ligand that binds intramolecularly to the receptor to trigger transmembrane signaling. This unique mechanism of activation would indicate that regardless of the activating protease, cleavage of PARs would unmask a tethered ligand sequence that would induce a similar active receptor conformation and signaling response. However, this is not the case. Recent studies demonstrate that PARs can be differentially activated by synthetic peptide agonists, proteases or through dimerization, that ultimately result in distinct cellular responses. In some cases, allosteric modulation of PARs involves compartmentalization in caveolae, plasma membrane microdomains enriched in cholesterol. Here, we discuss some mechanisms that lead to allosteric modulation of PAR signaling.
Keywords: Thrombin, GPCR, G protein, caveolae, palmitoylation, kallikriens, guanine nucleotide, SFLLRN, TFLLRNPNDK, fibroblast-to-myofibroblast
Mini-Reviews in Medicinal Chemistry
Title:Allosteric Modulation of Protease-Activated Receptor Signaling
Volume: 12 Issue: 9
Author(s): I. Canto, U. J.K. Soh and J. Trejo
Affiliation:
Keywords: Thrombin, GPCR, G protein, caveolae, palmitoylation, kallikriens, guanine nucleotide, SFLLRN, TFLLRNPNDK, fibroblast-to-myofibroblast
Abstract: The protease-activated receptors (PARs) are G protein-coupled receptors (GPCRs) that are uniquely activated by proteolysis. PARs mediate hemostasis, thrombosis, inflammation, embryonic development and progression of certain malignant cancers. The family of PARs include four members: PAR1, PAR2, PAR3 and PAR4. PARs harbor a cryptic ligand sequence within their N-terminus that is exposed following proteolytic cleavage. The newly formed PAR Nterminus functions as a tethered ligand that binds intramolecularly to the receptor to trigger transmembrane signaling. This unique mechanism of activation would indicate that regardless of the activating protease, cleavage of PARs would unmask a tethered ligand sequence that would induce a similar active receptor conformation and signaling response. However, this is not the case. Recent studies demonstrate that PARs can be differentially activated by synthetic peptide agonists, proteases or through dimerization, that ultimately result in distinct cellular responses. In some cases, allosteric modulation of PARs involves compartmentalization in caveolae, plasma membrane microdomains enriched in cholesterol. Here, we discuss some mechanisms that lead to allosteric modulation of PAR signaling.
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Cite this article as:
Canto I., J.K. Soh U. and Trejo J., Allosteric Modulation of Protease-Activated Receptor Signaling, Mini-Reviews in Medicinal Chemistry 2012; 12 (9) . https://dx.doi.org/10.2174/138955712800959116
DOI https://dx.doi.org/10.2174/138955712800959116 |
Print ISSN 1389-5575 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5607 |
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